Dominantly inherited Alzheimer's disease (AD) represents less than 1% of all cases of AD and is an attractive model for study because the responsible mutations have known biochemical consequences that are believed to underlie the pathological basis of the disorder. We will test three major hypotheses in this application. First, we hypothesize that there is a period of preclinical (presymptomatic) AD in individuals who are destined to develop early-onset dementia (gene carriers) that can be detected by changes in biological fluids and in neuroimaging correlates in comparison with individuals who will not develop early-onset dementia (noncarriers). Second, because all identified causative mutations for AD affect the normal processing of amyloid precursor protein (APR) and increase brain levels of amyloid-beta-42 (A[unreadable]42), we hypothesize that the sequence of preclinical changes initially will involve A[unreadable]42 (production and clearance;reduced levels in cerebrospinal fluid [CSF]), followed by evidence for cerebral deposition of A[unreadable]42 (amyloid imaging), followed by cerebral metabolic activity (functional imaging), and finally by regional atrophy (structural imaging). Finally, we hypothesize that the phenotype of symptomatic early-onset familial AD, including its clinical course, is similar to that of late-onset "sporadic" AD. We propose the following specific aims to test these hypotheses: 1. Establish an international, multicenter registry of individuals (mutation carriers and noncarriers;presymptomatic and symptomatic) who are biological adult children of a parent with a known causative mutation for AD in the APP, PSEN1, or PSEN2 genes in which the individuals are evaluated in a uniform manner at entry and longitudinally thereafter with standardized instruments. 2. In presymptomatic individuals, compare mutation carriers and noncarriers to determine the order in which changes in clinical, cognitive, neuroimaging, and biomarker indicators of AD occur prior to the occurrence of dementia. 3. In symptomatic individuals, compare the clinical and neuropathological phenotypes of ADAD to those of late-onset "sporadic" AD (using the data sets established by ADNI and by NACC). 4. Maintain the DCA, an integrated data base incorporating all information obtained from individuals in the registry to permit analyses within, between, and among the various data domains and also to disseminate the data to qualified investigators in a user-friendly manner. 5. Provide genetic counseling to all DIAN participants and, for those who after counseling wish to learn their mutation carrier status, provide genetic testing by Clinical Laboratory Improvement Amendments-approved laboratories.